The β-lactam type antibiotics, namely penicillins, cephalosporins, carbapenems, monobactams are frequently used antibiotics. It is known that β-lactamases produced by microorganisms hydrolyze the β-lactam ring thereby deactivating antibiotic activity. In order to inhibit the β-lactamases, β-lactamase inhibitors are administered in combination with antibiotics. These inhibitors function by binding to the β-lactamase enzymes more efficiently than the β-lactam antibiotic itself. This combination helps the antibiotic to exert its antibiotic effect without being degraded by the β-lactamase enzymes. Several antibiotic/β-lactamase inhibitor combinations exist in the market for example, Ampicillin/Sulbactam, Amoxicillin/Clavulanate, Ticarcillin/Clavulanate, Piperacillin/Tazobactam, etc. These β-lactam/β-lactamase inhibitor combination antibiotics are being used for the treatment of infections caused by bacteria producing β-lactamases excepting especially carbapenemases and inhibitor-resistant β-lactamases in the community and in the hospital setting.
A growing problem by the widespread use of antimicrobials especially β-lactam antibiotics is in the development of antimicrobial resistance. A major cause for antibiotic resistance is due to β-lactamases (e.g., carbapenemases, cephalosporinases, penicillinases, ESBLs, inhibitor-resistant β-lactamases, etc). Among many known β-lactamases, Carbapenemases (e.g., KPC, Sme, NMC-A, IMI, etc.) are recently identified, which are capable of hydrolyzing all classes of β-lactam antibiotics (Drawz, S. M. and Bonomo, R. A. Clin. Microbiol. Rev. 2010, 23(1), 160-201). These enzymes are known for their role in multidrug resistance (MDR). In view of the pressing need in the development of effective β-lactamase inhibitor (BLI) against the evolving β-lactamases, our research efforts in identifying potential BLIs resulted in the compound of formula (I).
To address the need for proper diagnostic method for specific detection of β-lactamases, diagnostic method was identified using the compounds of formula (I).
Among many β-lactamase inhibitors that are known in the literature, compounds of formula (A) are disclosed in U.S. Pat. No. 4,562,073,
wherein R1 is hydrogen or trialkylsilyl; R2 is hydrogen, trialkylsilyl or COOR2′ wherein R2′ is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton-4-yl, gamma-butyrolacton-4-yl, halogenated C1-6 alkyl substituted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted benzyl, benzhydryl, tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, trichlorosilyl, (5-substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group for forming a pharmaceutically acceptable salt; and R3 has the same meaning as above R2′.
Our U.S. Pat. No. 7,687,488 B2 (Indian equivalent IN 1217CHE2006) disclosed compounds of the formula (B). These compounds were shown to potentiate the activity of antibiotics.

wherein A=C or N; Het is a three- to seven-membered heterocyclic ring; R1 represents carboxylate anion or —COOR4 wherein R4 represents hydrogen, carboxylic acid protecting group or a pharmaceutically acceptable salt; R2 and R3 may be same or different and independently represent hydrogen, halogen, amino, protected amino or optionally substituted alkyl, alkenyl, alkynyl and the like; R is represented by substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, oxo, heterocyclyl, heterocyclylalkyl groups.
There is a widespread need for β-lactamase inhibitors which are capable of inhibiting the β-lactamase enzymes, in particular, carbapenemases producing multidrug resistant bacteria. Moreover, there is a unmet medical need for combination drugs in antibiotics, specifically β-lactam antibiotics and β-lactamase inhibitors which overcome the bacterial resistance.
Objectives
One objective herein is to use the β-lactam compounds of the formula (I) as β-lactamase inhibitor in combination with suitable antibiotics for treating infection caused by bacteria producing β-lactamases like carbapenemases, cephalosporinases, penicillinases, ESBLs, inhibitor-resistant β-lactamases, ESBLs and the like.
Another objective herein is to provide a pharmaceutical composition with the compounds of formula (I) in combination with suitable antibiotics.
Yet another objective herein is to provide a method of treating or preventing bacterial infection in a host, typically an animal and most typically a human, including administering to the host a therapeutic amount of compound of formula (I) or a pharmaceutically acceptable salt and/or prodrug therein along with β-lactam antibiotics.
Another objective herein is to provide a diagnostic reagent for the detection of β-lactamases. The said β-lactamases belong to the families of KPC (e.g., KPC-2, KPC-3) & ESBL (e.g., SHV18) producing Enterobacteriaceae.
One more objective herein is to restore/potentiate the activity of antibiotics especially β-lactam antibiotics such as Penicillins, Cephalosporins, Carbacephem, Oxacephem, Carbapenems, Penams, Cephamycins, Penems and Monobactams towards carbapenemases and ESBLs by combining with compound of formula (I).
It is therefore an object of the present invention to provide a compound for inhibiting β-lactamase; and/or a pharmaceutical composition comprising said compound; and/or an improved method for inhibiting β-lactamase in a cell; and/or an improved method for the treatment and/or prevention of a condition mediated by β-lactamase; and/or an improved method for the treatment and/or prevention of a bacterial infection along with β-lactam antibiotic; and/or to restore/potentiate the activity of antibiotics; or at least to provide the public with a useful choice.